Multiple Pathways for Repair of DNA Double-Strand Breaks in Mammalian Chromosomes

Lin, Yunfu; Lukácsovich, Tamás; Waldman, Alan S.

doi:10.1128/mcb.19.12.8353

Cited by 128 publications

(132 citation statements)

References 53 publications

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“…97,103 However, the clearest demonstration of the link between DNA repair mechanisms and illegitimate integration comes from studies that find that inducing a chromosomal DSB at a defined genomic locus (by expression of a site-specific endonuclease) promotes illegitimate integration at that site. 29,108 These experiments clearly show that most integration events are probably mediated by the cellular DNA repair machinery.…”

Section: Proposed Mechanisms Of Illegitimate Dna Integrationmentioning

confidence: 80%

Illegitimate DNA integration in mammalian cells

2003

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Foreign DNA integration is one of the most widely exploited cellular processes in molecular biology. Its technical use permits us to alter a cellular genome by incorporating a fragment of foreign DNA into the chromosomal DNA. This process employs the cell's own endogenous DNA modification and repair machinery. Two main classes of integration mechanisms exist: those that draw on sequence similarity between the foreign and genomic sequences to carry out homology-directed modifications, and the nonhomologous or 'illegitimate' insertion of foreign DNA into the genome. Gene therapy procedures can result in illegitimate integration of introduced sequences and thus pose a risk of unforeseeable genomic alterations. The choice of insertion site, the degree to which the foreign DNA and endogenous locus are modified before or during integration, and the resulting impact on structure, expression, and stability of the genome are all factors of illegitimate DNA integration that must be considered, in particular when designing genetic therapies.

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Section: Proposed Mechanisms Of Illegitimate Dna Integrationmentioning

confidence: 80%

Illegitimate DNA integration in mammalian cells

2003

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“…There can be either small changes in sequence or larger changes (which are typically deletions) when there is a deficiency in one or more components of the Ku-dependent repair pathway. Microhomologies may or may not be involved in the formation of the junction (66). Recently, there is evidence that error-free and error-prone end-joining have different genetic requirements (67), further supporting the idea that there is more than one pathway of NHEJ.…”

Section: Brca1 and Nhejmentioning

confidence: 80%

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang

Powell

2005

Molecular Cancer Research

185

154

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The tumor suppressor gene BRCA1 was cloned in 1994 based on its linkage to early-onset breast and ovarian cancer. Although the BRCA1 protein has been implicated in multiple cellular functions, the precise mechanism that determines its tumor suppressor activity is not defined. Currently, the emerging picture is that BRCA1 plays an important role in maintaining genomic integrity by protecting cells from double-strand breaks (DSB) that arise during DNA replication or after DNA damage. The DSB repair pathways available in mammalian cells are homologous recombination and nonhomologous end-joining. BRCA1 function seems to be regulated by specific phosphorylations in response to DNA damage and we will focus this review on the roles played by BRCA1 in DNA repair and cell cycle checkpoints. Finally, we will explore the idea that tumor suppression by BRCA1 depends on its control of DNA DSB repair, resulting in the promotion of error-free and the inhibition of error-prone recombinational repair.

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“…During religation, exogenous DNA may be captured in the chromosome, leading to insertion of DNA into the genome. In eukaryotes, DNA inserted into the genome by NHEJ during evolution may include foreign DNA fragments such as mitochondrial DNA, transposable elements, and viral DNA (Moore and Haber 1996;Ricchetti et al 1999;Lin and Waldman 2001a;Lin and Waldman 2001b;Nakai et al 2003;Hazkani-Covo and Covo 2008). The classical eukaryotic NHEJ machinery includes the KU70/80 heterodimer (KU), XRCC4, Ligase IV, and DNA-PKcs proteins (Bassing and Alt 2004;Lieber et al 2004).…”

Section: Recent Lgt Between Distantly Related Speciesmentioning

confidence: 99%

Directed networks reveal genomic barriers and DNA repair bypasses to lateral gene transfer among prokaryotes

Popa

Hazkani‐Covo²,

Landan³

et al. 2011

Genome Res.

224

204

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Lateral gene transfer (LGT) plays a major role in prokaryote evolution with only a few genes that are resistant to it; yet the nature and magnitude of barriers to lateral transfer are still debated. Here, we implement directed networks to investigate donor-recipient events of recent lateral gene transfer among 657 sequenced prokaryote genomes. For 2,129,548 genes investigated, we detected 446,854 recent lateral gene transfer events through nucleotide pattern analysis. Among these, donor-recipient relationships could be specified through phylogenetic reconstruction for 7% of the pairs, yielding 32,028 polarized recent gene acquisition events, which constitute the edges of our directed networks. We find that the frequency of recent LGT is linearly correlated both with genome sequence similarity and with proteome similarity of donor-recipient pairs. Genome sequence similarity accounts for 25% of the variation in gene-transfer frequency, with proteome similarity adding only 1% to the variability explained. The range of donor-recipient GC content similarity within the network is extremely narrow, with 86% of the LGTs occurring between donor-recipient pairs having #5% difference in GC content. Hence, genome sequence similarity and GC content similarity are strong barriers to LGT in prokaryotes. But they are not insurmountable, as we detected 1530 recent transfers between distantly related genomes. The directed network revealed that recipient genomes of distant transfers encode proteins of nonhomologous end-joining (NHEJ; a DNA repair mechanism) far more frequently than the recipient lacking that mechanism. This implicates NHEJ in genes spread across distantly related prokaryotes through bypassing the donor-recipient sequence similarity barrier.

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Multiple Pathways for Repair of DNA Double-Strand Breaks in Mammalian Chromosomes

Cited by 128 publications

References 53 publications

Illegitimate DNA integration in mammalian cells

Illegitimate DNA integration in mammalian cells

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Directed networks reveal genomic barriers and DNA repair bypasses to lateral gene transfer among prokaryotes

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